Project Summary Humans, like other animals, regularly modify behavior based on environmental context. This relies on the ability to discriminate between environments and develop strategies for maximizing rewards (or minimizing punishment) in a context-specific manner. A breakdown in this ability to change behavior depending on environment is prominent in dementia and Alzheimer's disease. Our central objective is to identify the specific neuronal circuits and activity dynamics required for acquiring goal-oriented behaviors in novel environments. We focus on the hippocampus, a region critical for discriminating between environments and necessary for encoding certain types of behavior. Our central hypothesis is that cell-type specific inhibitory circuits regulate the pyramidal network dynamics that encode goal-oriented behavior. Specifically, we use in vivo two-photon calcium imaging to visualize the activity of genetically-defined subsets of hippocampal CA1 neurons as mice complete goal-oriented tasks in virtual reality (VR) environments, using water rewards for motivation (Arriaga and Han, J. Neurosci., 2017). With this system, we recently found that both parvalbumin (PV)- and somatostatin (SOM)-expressing inhibitory interneurons are strongly suppressed in novel environments, with gradual recovery of activity over days as task performance increases (Arriaga and Han, eLife, 2019). In Aim 1, we will use a combination of imaging, behavior, and correlative functional and immunolabeling microscopy to define putative disinhibitory VIP+ neurons activated in novel environments. In Aim 2, we will define the kinetics of excitatory network reorganization in novel environments during goal-oriented behavior. If inhibitory activity plays a major role in controlling the encoding of information in excitatory networks, we should see similar kinetics in activity dynamics across the two networks, i.e. slow stabilization over days. We will track individual pyramidal neurons during task-engaged behavior in novel environments to define activity dynamics of the excitatory network. To facilitate this goal, we have developed a neural network-based decoder that tracks the contribution of individual neurons to population position coding across days. In Aim 3, we will determine the necessity of inhibition suppression and disinhibition activation for goal-oriented behavior and pyramidal network reconfiguration. We will test this by chemogenetically restoring inhibitory SOM+ and PV+ interneuron activity (separately), or silencing PV+ neurons, in novel environments and compare task performance with control mice. To illuminate possible circuit mechanisms downstream of inhibitory activity manipulation, we will image excitatory neuron activity to evaluate alterations in network reorganization as defined in Aim 2. This contribution is significant because it promises to link cell type-specific inhibitory activity with novelty-induced, pyramidal network reorganization and goal-oriented behavior in vivo. These studies may lead to new circuit- targeted approaches to enhance network function for the treatment of behavioral impairment associated with many cognitive disorders and neurodegenerative diseases.